Prior to Edward Jenner's demonstration in 1796 that immunization with cowpox protected against smallpox infection, virtually everyone contracted smallpox with mortality as high or higher than 30%. A global campaign using vaccinia immunization for protection from smallpox infection resulted in the eradication of smallpox in 1977. Subsequently the WHO recommended that all countries cease vaccination and laboratory stocks be destroyed or transferred to one of two repositories at the CDC in the United States or the Institute of Virus Preparations in Moscow, Russia. Routine vaccination in the United States has not occurred for more than thirty years. Therefore, the vast majority of the population is at risk of smallpox infection. Just as smallpox was used as a bioweapon prior to the development of vaccination, it currently represents a potential biological weapon with the majority of the world population at risk. Vaccination within the first few days after exposure is effective at preventing infection in some with a significant decrease in mortality. However, there are rare and serious complications in some vaccinated individuals. The vaccination is contraindicated in a number of groups of people. Vaccinia immune globulin (VIG) has been used as prophylaxis for treating individuals for which contra indications exist for smallpox vaccine and for treatment of those with complications of vaccinations. With the threat of smallpox being used as an agent of bioterrorism, it is prudent to develop alternatives for the use of VIG for prophylaxis and treatment. Supplies of VIG are scarce given that individuals have not been systematically vaccinated for more than 30 years. Furthermore, the validation and safety of VIG remains an issue. Therefore, we propose to generate human monoclonal antibodies as a replacement for VIG. Monoclonal antibodies can be produced with exquisite specificity and can be modified to enhance functional activity. The use of fully human monoclonal antibodies eliminates problems associated with xenogeneic, chimeric or humanized antibodies which include immunogenicity, biological half-life, and inefficient effector function. The development of a cocktail of human monoclonal antibodies that neutralize virus and/or mediate antibody-dependent cellular cytotoxicity can serve as a safe, effective replacement for VIG.